L0301P91 - Antibiotics 1
Infection Cycle Infections *person to person *nosocomial infections **hospital-acquired **often are antibiotic resistant *zoonotic infections **transmitted from animals to humans **difficult to control Controlling Infections *affects these stages of the infection cycle: **portal of exit **mode of transportation **portal of entry *accomplished by: **improve sanitation and hygiene **control animals and pests **vaccination **“personal protection” - education Pharmacotherapy *when prevention fails *targets these stages of the infection cycle: **susceptible host **pathogenic organism **reservoir of infection *symptomatic **helps alleviate symptoms **body should be able to remove pathogen on its own *specific **targets the pathogen Chemotherapy *the use of chemicals to treat or control disease caused by infectious agents Ideal Chemotherapeutic Agent *minimal adverse effects *easy route of admission *effective elimination of the target **gets to the target site **stays at the target site **destroys pathogenic organisms/cells (or facilitate their destruction) **can be eliminated from the body *high therapeutic window (not easily toxic) *cheap *easily manufactured Patient-Drug-Pathogen Interaction *effect of drug on the patient *effect of the pathogen on the patient *effect of drug on the pathogen Pharmacokinetics *ensures the bacteria is exposed to the appropriate drug and that it is effective *important parameters: **volume of distribution (Vd) **maximum (peak) concentration (Cmax) **time to maximum concentration (Tmax) **half life (t 1⁄2) Pharmacodynamics *how does a drug act to affect the pathogen *concepts include: **drug target (mechanism of action) **spectrum of activity **bacteriostatic / bactericidal action **Minimum Inhibitory Concentration (MIC) **Minimum Bactericidal Concentration (MBC) **time-dependent killing **concentration-dependent killing **post-antibiotic effect (PAE) Selective Toxicity *determines how good a drug is at its “job” *toxic to only the target cells/pathogen *achieving selective toxicity **requires finding a unique target that is not present in the human body/cells Targets for Selective Toxicity *cell wall *folate metabolism *protein synthesis *nucleic acid synthesis Bacterial Cell Wall *is necessary to maintain integrity of the bacteria under osmotic pressures *different bacteria have different compositions of peptidoglycan **gram-positive cell wall is mainly composed of peptidoglycan **while peptidoglycan in mycobacteria are hidden beneath other layers Targets *transglycosidase (transglycosylase) action **enzymes that catalyse the polymerisation of carbohydrate chains of peptidoglycan **e.g. glycopeptides - vancomycin *transpeptidase action **enzymes that are involved with cross-linking peptidoglycan layers in order to strengthen the cell wall **e.g. β-lactams ***penicillins - amoxycillin ***cephlasporins - cephalexin *mycolic acid synthesis **essential component of cell walls of mycobacterium **e.g.: isoniazid Folate Metabolism *bacteria must synthesis their own folate (from para-aminobenzoic acid) which is involved in DNA synthesis Targets *the enzyme involved in folate synthesis *e.g. sulphonamides (sulphones) - sulfamethazole *dihydroxyfolate (DHF) reductase **enzyme involved in converting folate into components necessary for DNA synthesis **e.g. trimethoprim Protein Synthesis *compared to eukaryotes, prokaryotic ribosomes are different in structure *have two components: 30S and 50S Targets *50S inhibitors **interfere with movement of ribosome along mRNA ***e.g. macrolides - erythromycin **inhibit transfer of peptide from tRNA ***e.g. chloramphenicol *30S inhibitors **cause misreading of mRNA = wrong production of proteins ***e.g. aminoglycosides - gentamicin **interfere with binding of tRNA to mRNA-ribosomal complex ***e.g. tetracyclines - doxycycline Nucleic Acid Synthesis *inhibit DNA synthesis **e.g. ***fluroquinolones - ciprofloxacin ***nitroimidazoles - metronidazole *inhibit RNA synthesis **e.g. rifampicin Spectrum of Activity *number of microbes sensitive to the action of an antimicrobial agent *narrow spectrum **more targeted effects but not always available **e.g. isoniazid *broad spectrum **e.g. tetracyclines Bacteriostatic vs Bactericidal Drugs Bacteriostatic: *chloramphenicol, erythromycin, sulphonamides, trimethoprim, tetracyclines Bactericidal: *aminoglycosides, β-lactams, vancomycin, rifampicin, metronidazole Bacterial Growth In Vitro *growth plateaus due to competition for nutrients and space *effects of antibacterial agents: Preference *in a petri dish, bacteria which have been treated with bacteriostatic drugs can continue to grow after removal of the drug *in a human, bacteriostatic drugs work in cooperation with the immune system and therefore are not less effective *considerations in the choosing of a drug: **patient’s immune system competency ***bacteriostatic drugs would not work for immunosuppressed patients **release of endotoxins from dying bacteria ***bacteriostatic may be preferred to prevent build up of toxins which may cause inflammatory reactions Detecting Antibacterial Action *MIC - minimum inhibitory concentration  = lowest concentration that inhibits growth *MBC - minimum bactericidal concentration = lowest concentration that reduces number *MEC - minimum effective plasma concentration in order to achieve the desired therapeutic outcome Bacterial Growth In Vivo *aim to administer dosage that would be at least above MIC, and if possible above MBC *this concentration in a lab would be different to the concentration within a person *therefore must calculate the MEC Dosing Regimens *consider relationship between time/dose *time - how often does the drug need to be administered *dose - how much of the drug is to be administered each time to maintain MEC For some drugs, their effect depends on: *Time-Dependent Effect **time that drug > MEC **∴ increasing dose ≠ increasing effect **e.g. β-lactams *Concentration-Dependent Effect **peak drug that the bacteria is expose to **limit of peak drug is determined by: ***toxicity of the drug **∴ increasing dose = increasing effect **e.g. aminoglycosides, fluroquinolones Post-Antibiotic Effect *continued suppression of bacterial growth after antibacterial serum levels have dropped below MEC *presence and/or duration is influenced by: **type of organism **type of antimicrobial **concentration of antimicrobial **duration of antimicrobial exposure **antimicrobial combinations *can influence the treatment regimen Antibiotic Resistance *resistance to the effects of a specific drug = reduction in effectiveness *can lead to: **reduced usefulness of a drug ***resort to other drugs which often have more adverse effects **increased morbidity/mortality of infection *caused by exposure to sub-lethal doses via normal and indiscriminate use **e.g. wrong drug; dose too low; ‘course’ not completed Types *intrinsic - the drug just doesn’t work on the bacteria as it does not have the target *acquired - sharing of resistant genes between bacteria Mechanisms *target site may be altered *enzymatic inactivation of the drug *decreased uptake **drug cannot penetrate the bacterial wall **bacteria has efflux channels *“bypass” pathways **process that was originally inhibited can occur via another method Dosing Principles *drugs must gain access to site of infection *route of administration depends on: **pharmacokinetic profile of drug **site of infection **patient compliance *dose depends on: **minimum effective concentration **volume of distribution of the drug *frequency of administration depends on: **pharmacokinetic profile (t1/2 / toxicity) **patient factors **post-antibiotic effect Common Adverse Effects *tend to be worse in patients who take high doses for extended periods of time *specific effects include: **gastrointestinal upsets - nausea, vomiting **ototoxicity (hearing system) **nephrotoxicity **drug interactions **allergic/hypersensitivity reactions ***rashes to anaphylaxis **superinfection - mostly associated with broad spectrum antibiotics Superinfections *a new infection occurring in a patient having a preexisting infection *e.g. Clostridium difficile - normal GI bacteria **infection after antibiotics due to upset in balance of pathogenic and nonpathogenic Therapeutic Index Combination Chemotherapy *combination therapy is rarely used for bacterial infections **to avoid killing off normal flora *maybe required: **if concomitant infections **if unsure of organism (awaiting pathology report) **to decrease the development of resistance **to reduce drug-induced toxicity **to achieve a potentiating effect  i.e. increase the rate of killing even with lower doses of both drugs ***e.g.: β-lactam + aminoglycoside ****AG aids entry of BL into the bacteria ***e.g.: sulphonamides + DHF reductase inhibitors ****sequential blockade = double effect  Prophylaxis *use before potential exposure or after a known/suspected exposure that is potentially fatal **e.g.: travel; before or after surgery *must weigh up risk vs benefit *not used all the time due to adverse effects of drug are often worse than the infection itself, as well as antibiotic resistance Antimicrobial Creed *'M' = Microbiology guides therapy where possible *'I' = Indications should be evidence-based *'N' = Narrowest spectrum required *'D' = Dosage individualised - appropriate to the site and type of infection *'M' = Minimise duration of therapy *'E' = Ensure oral therapy where appropriate